α1-Adrenergic receptor subtypes: non-identical triplets with different dancing partners?

Hague, Chris; Chen, Zhongjian; Uberti, Michelle A.; Minneman, Kenneth P.

doi:10.1016/j.lfs.2003.07.008

Cited by 40 publications

(38 citation statements)

References 47 publications

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“…In the past, development of therapeutic compounds that target ␣ 1 -ARs has been driven by their important roles in the regulation of hypertension, benign prostatic hypertrophy, and nasal congestion (1,11). However, few drugs have been produced that can adequately differentiate between ␣ 1 -AR subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular cloning and pharmacological studies have identified three subtypes of ␣ 1 -ARs: ␣ 1A -, ␣ 1B -, and ␣ 1D -ARs (3)(4)(5)(6)(7)(8)(9)(10). Although all three ␣ 1 -AR subtypes signal through the same G q/11 signaling pathway (11), ␣ 1 -AR subtypes can differ in their tissue distributions (1), cellular localization (12,13), activation of transcriptional responses (14), and association with intracellular proteins (15)(16)(17), suggesting that ␣ 1 -AR subtypes perform specific physiological functions. Furthermore, recent data obtained from both ␣ 1 -AR overexpressed (18 -21) and knockout mice (22)(23)(24)(25) indicate that ␣ 1 -ARs play important physiological roles in the cardiovascular system and central nervous system.…”

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confidence: 99%

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Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Chen

Rogge

Hague

et al. 2004

Journal of Biological Chemistry

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The 19-amino acid conopeptide ( -TIA) was shown previously to antagonize noncompetitively ␣ 1B -adrenergic receptors (ARs). Because this is the first peptide ligand for these receptors, we compared its interactions with the three recombinant human ␣ 1 -AR subtypes (␣ 1A , ␣ 1B , and ␣ 1D ). Radioligand binding assays showed that -TIA was 10-fold selective for human ␣ 1B -over ␣ 1A -and ␣ 1D -ARs. As observed with hamster ␣ 1B -ARs, -TIA decreased the number of binding sites (B max ) for human ␣ 1B -ARs without changing affinity (K D ), and this inhibition was unaffected by the length of incubation but was reversed by washing. However, -TIA had opposite effects at human ␣ 1A -ARs and ␣ 1D -ARs, decreasing K D without changing B max , suggesting it acts competitively at these subtypes. -TIA reduced maximal NE-stimulated [ 3 H]inositol phosphate formation in HEK293 cells expressing human ␣ 1B -ARs but competitively inhibited responses in cells expressing ␣ 1A -or ␣ 1D -ARs. Truncation mutants showed that the amino-terminal domains of ␣ 1B -or ␣ 1D -ARs are not involved in interaction with -TIA. Alanine-scanning mutagenesis of -TIA showed F18A had an increased selectivity for ␣ 1B -ARs, and F18N also increased subtype selectivity. I8A had a slightly reduced potency at ␣ 1B -ARs and was found to be a competitive, rather than noncompetitive, inhibitor in both radioligand and functional assays. Thus -TIA noncompetitively inhibits ␣ 1B -ARs but competitively inhibits the other two subtypes, and this selectivity can be increased by mutation. These differential interactions do not involve the receptor amino termini and are not because of the charged nature of the peptide, and isoleucine 8 is critical for its noncompetitive inhibition at ␣ 1B -ARs.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Chen

Rogge

Hague

et al. 2004

Journal of Biological Chemistry

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“…Both mLTD and NE LTD require presynaptic activity and NMDA receptor (NMDAR) activation, indicating that they share mechanistic properties. In addition, M 1 and ␣1 receptors couple to the same G-protein, G␣q (Porter et al, 2002;Hague et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Coactivation of M₁Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

et al. 2008

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Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M 1 or adrenergic ␣1 receptors induces activity-and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common G␣q-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M 1 and ␣1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signalregulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M 1 and ␣1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M 1 and ␣1 receptors could function to induce long-term changes in synaptic function important for cognition.

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“…This has been facilitated by the availability of increasingly selective antagonists for individual subtypes, especially for the a 1A and a 1D , as well as knockout (KO) mice lacking either a 1A , a 1B or a 1D adrenoceptors (Hague et al, 2003).In some tissues, such as heart or blood vessels, multiple a 1 subtypes are present and produce the same functional response, although the dominant subtype can vary between species or particular blood vessels (Hrometz et al, 1999). In other cases, such as in most urogenital smooth muscles, the response is mediated primarily by a single subtype (a 1A ) independent of species (Ruffolo & Hieble, 1999).…”

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α₁‐Adrenoceptor subtype substitution in knockout mice

Hieble

2004

British J Pharmacology

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Since the discovery of a 1 -adrenoceptor subtypes, there has been continued interest in the identification of their functional roles. This has been facilitated by the availability of increasingly selective antagonists for individual subtypes, especially for the a 1A and a 1D , as well as knockout (KO) mice lacking either a 1A , a 1B or a 1D adrenoceptors (Hague et al., 2003).In some tissues, such as heart or blood vessels, multiple a 1 subtypes are present and produce the same functional response, although the dominant subtype can vary between species or particular blood vessels (Hrometz et al., 1999). In other cases, such as in most urogenital smooth muscles, the response is mediated primarily by a single subtype (a 1A ) independent of species (Ruffolo & Hieble, 1999). Depending on the species, the dominant a 1 -adrenoceptor mediating metabolic responses in the liver is either a 1A (human, cat, dog, rabbit) or a 1B (rat, mouse, hamster). In the monkey, hepatic a 1A and a 1B adrenoceptors both contribute (GarciaSainz et al., 1996). In this issue of British Journal of Pharmacology, Deighan et al. (2004) show that, in a 1B KO mice, the function of the hepatic a 1B adrenoceptor can be assumed by the a 1A .Radioligand-binding assays show RS100329, a selective a 1A antagonist, to have 30-fold greater affinity for a 1 -adrenoceptors in hepatocytes from the KO animals (pK i ¼ 9.3) than in WT animals (pK i ¼ 7.8). In contrast, the selective a 1D antagonist BMY 7378 had low affinity in both WT and KO mice (pK i ¼ 6.3 and 6.2, respectively).At 4 months of age, the liver from a 1B KO mice had a substantial a 1 -receptor binding (30 fmol mg À1 protein), although less than WT mice of the same age (50 fmol mg À1 protein). However, 3-month-old KO mice had almost no hepatic a 1 -adrenoceptor binding. This would indicate that replacement of the missing a 1B adrenoceptor by the a 1A is a relatively slow process, and suggest that, in general, comparisons of receptor density between WT and KO mice should be made at multiple time points.Based on multiple literature reports, it is now clear that a 1 -adrenoceptors are not confined to the cell membrane, and that the subcellular localization can differ between subtypes (Mackenzie et al., 2000;Stanasila et al., 2003;Hague et al., 2004). Deighan et al. (2004) show that the distribution of a 1A adrenoceptors in KO mice is identical to that of the a 1B in WT mice, consistent with the ability of the two subtypes to mediate the same physiological function.This

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α1-Adrenergic receptor subtypes: non-identical triplets with different dancing partners?

Cited by 40 publications

References 47 publications

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Coactivation of M₁Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

α₁‐Adrenoceptor subtype substitution in knockout mice

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α1-Adrenergic receptor subtypes: non-identical triplets with different dancing partners?

Cited by 40 publications

References 47 publications

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Coactivation of M1Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

α1‐Adrenoceptor subtype substitution in knockout mice

Contact Info

Product

Resources

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Coactivation of M₁Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

α₁‐Adrenoceptor subtype substitution in knockout mice